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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Medtronic, Inc. 03-Jul-07

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration

 

Minneapolis District Office
Central Region
212 Third Avenue South
Minneapolis, MN 55401
Telephone: (612) 758-7133
FAX: (612) 334-4142


July 3, 2007

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Refer to MIN 07 - 18

Arthur D. Collins, Jr.
Chairman of the Board and Chief Executive Officer
Medtronic, Inc.
710 Medtronic Parkway
Minneapolis, Minnesota 55432

Dear Mr. Collins:

During a limited inspection of your establishment, Medtronic Neuromodulation1, located at 800 53rd Avenue Northeast, Minneapolis, Minnesota, 55421, on November 21, 2006, through January 24, 2007, investigators from the Food and Drug Administration (FDA) determined that your establishment manufactures implantable drug infusion and neurostimulation products. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or any function of the body.

Our inspection revealed that your devices are adulterated within the meaning of section 501(h) of the Act [21 U.S.C. § 351(h)], in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations, (21 CFR) Part 820. We received responses from Mr. George Aram, Vice President of Quality and Compliance, dated February 23, 2007, March 30, 2007, April 30, 2007, and June 4, 2007, concerning our investigators' observations noted on the Form FDA 483, List of Inspectional Observations, that was issued to officials at your establishment. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to:

Failure to implement complaint handling procedures to ensure that all complaints are evaluated to determine whether the complaint represents an event that must be filed as a Medical Device Report under 21 CFR Part 803, as required by 21 CFR 820.198(a)(3).

It is our understanding that your establishment documents product complaints in your Product Comment Reporting (PCR) system. During the inspection, our investigators found on site several medical and/or scientific literature articles concerning adverse events relating to your devices that had not been entered into your PCR system and evaluated for reportability under 21 CFR Part 803 (Medical Device Reporting). See Observation #4 in the Form FDA 483 issued on January 24, 2007. A manufacturer has an obligation to submit an MDR report under Part 803 once it becomes aware of information, from any source, that reasonably suggests that a device it markets may have caused or contributed to an MDR reportable event (21 CFR 803.50). Therefore, your firm should have considered whether the events described in these medical and/or scientific articles would represent reportable events under 21 CFR Part 803.

In response to this observation, your firm drafted a new literature review SOP that includes proactive search methods for selecting relevant articles and reviewing them to determine their reportability. As part of your response, you also provided a new work instruction entitled "Medical Device Reporting" to facilitate the implementation of the new literature review SOP. This portion of your response appears to be adequate and will be further evaluated at a future inspection of your facility.

Your responses also state that Medtronic Neurological met with CDRH, Office of Surveillance and Biometrics (OSB), on February 2, 2007, to discuss retrospective reporting of MDR reports based on scientific literature. Your firm states that you [redacted]

Our inspection revealed that your devices are misbranded under section 502(t)(2) of the Act [21 U.S.C. § 352(t)(2)], in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act (21 U.S.C. § 360i), and 21 CFR Part 803--Medical Device Reporting (MDR) regulation. Significant deviations include, but are not limited to:

Failure to submit MDR reports within 30 days of receiving or otherwise becoming aware of information that reasonably suggests that a marketed device may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1).

Medtronic failed to submit MDR reports for serious injury adverse events that were reported by or confirmed by a health care professional, or that were reported by a patient or a patient's family member. Examples of this violation include, but are not limited to, the following PCRs:

58709, 235359, 258561, 234149, 183288, 202853, 267989, 55251, 94553, 119033, 180984, 246172, 255091, 277026, 191620, 95901, 171432, 196649, 248557, 189519, 167978, 61760, 95681, 170773, 186498, 187587, 190010, 196714, 202096, 206578, 222730, 250677, 267713, 248978, 221032, 250099, and 269319.

Many of these PCRs involve a granuloma or inflammatory mass at or near the distal tip of the intrathecal catheter used with the SynchroMed pump, which are reportable as serious injuries. Some of these were surgically removed and some of the patients reported increased pain, tingling sensation in the legs, partial paralysis, total lower limb paralysis and other gait problems resulting from the granuloma or inflammatory mass. Some of the PCRs included a fracture of the intrathecal catheter. It is important to note that the MDR regulation also provides for the submission of a malfunction MDR for events in which the information reasonably suggests that a device you market has malfunctioned and would be likely to cause or contribute to a reportable death or serious injury if the malfunction were to recur. Your firm should have considered whether the failures reported in the PCRs referenced above would have constituted reportable events under 21 CFR Part 803.

Your firm also failed to submit MDR reports within 30 days of becoming aware of literature articles that referenced problems to which your devices may have caused or contributed. These include, but are not limited to, articles by Deer, McMillan et al., Hu et al., Kofler et al., and Loughrey et al. These articles included, among other things, information on pump malfunctions, catheter separation or fracture, and inflammatory masses and granulomas.

In addition, during the inspection of your facility, our investigators collected abstracts of several literature articles. The articles associated with these abstracts must be reported as MDRs if they discuss deaths, serious injuries, or malfunctions of your devices that would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur.

Your firm's responses indicate that you interpreted the MDR regulation to mean that any consumer self-reported events were not MDR reportable unless separately confirmed by a Health Care Professional (HCP). This interpretation of the MDR regulation is incorrect. Consumer self-reported events do not have to be confirmed by a HCP in order to determine reportability. Under 21 CFR 803.50, a firm has 30 calendar days after the day it receives or otherwise becomes aware of information, from any source, that reasonably suggests that a device it markets may have caused or contributed to an MDR reportable event. If, in the process of conducting an investigation, your firm contacts an HCP for additional information, then the additional information can be used by the firm to help make a determination about the MDR reportability of the consumer complaint.

Your responses also state that the MDR Work Instruction was revised to include a requirement to assess consumer self-reported events (whether or not confirmed by a HCP) and catheter events for MDR reportability. A copy of this revised procedure was provided as part of your responses. Your revised work instruction appears to adequately address our concern regarding the reporting of consumer self-reported events. However, this corrective action will be further assessed at a future inspection of your facility.

Our inspection further revealed that your devices are misbranded under section 502(t)(2) of the Act [21 U.S.C. § 352(t)(2)], in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 806 - Reports of Corrections and Removals regulation. Significant deviations include, but are not limited to:

A correction or removal conducted to reduce a risk to health posed by a device was not reported in writing to FDA, as required by 21 CFR 806.10(a)(1).

In July 2003 your establishment sent a letter with an enclosed "EDUCATIONAL BRIEF," entitled "Information about Inflammatory Mass," to SynchroMed customers (physicians). Also enclosed were reprints of two articles published in the December 2002 issue of Pain Medicine and revised labeling for the SynchroMed Technical Manual. FDA defines a "correction" in 21 CFR 806.2(d) as " . . .the repair, modification, adjustment, relabeling, destruction, or inspection (including patient monitoring) of a device without its physical removal from its point of use to some other location." FDA believes that the July 2003 Educational Brief, which was sent to all customers using SynchroMed pumps, meets the definition of "correction" in that the letter provided updated labeling to customers for devices that were already in distribution.

The FDA also believes that the July 2003 Educational Brief is a reportable correction under 21 CFR 806.10(a) (1) in that the letter contained specific information intended to reduce the risk to health posed by the device. For example, the July 2003 Educational Brief specifically states that "[i]f an inflammatory mass is detected in its clinical course, prompt discontinuation of opioid delivery into the mass may cause it to shrink or disappear without the need for surgical removal." The letter also specifically recommends catheter replacement, repositioning, and other interventional procedures, depending on the patient's clinical condition. These recommendations were neither included in the pump's original labeling, nor conveyed to customers in a January 2001 communication regarding inflammatory masses.

Additionally, the July 2003 Educational Brief contained new "Post implant" warnings that suggest that clinicians should routinely monitor patients for prodromal clinical signs or symptoms of inflammatory mass such as change in character, quality or intensity of pain; reports of new radicular pain, especially at or near the dermatomal level of the catheter tip; frequent or large escalations of daily drug dose to maintain the analgesic effect; and dose escalations that may only temporarily alleviate the patient's increasing pain. These new warnings were not included in the January 2001 letter or the pump's original technical manual.

Furthermore, the journal articles included with the July 2003 Educational Brief stated with regard to adverse event reporting that 41 adverse events regarding inflammatory mass were identified as of November 2000 (conveyed to customers in the January 2001 letter). The articles also state that an additional 51 events were identified after the 2001 letter had been distributed to customers. The articles suggest that the number of new adverse events has more than doubled in one year of reporting. It is noteworthy that during the most recent inspection of your facility, your firm calculated the current rate of inflammatory masses to be approximately [redacted] events per [redacted] implants. This figure, which has not yet been communicated to your customers, suggests that the risk of inflammatory masses occurring at or near the tip of intrathecal catheters used with SynchroMed pumps is [redacted] greater than the [redacted] rate indicated in the January 2001 letter.

Your firm's responses to this observation stated that the July 2003 Inflammatory Mass "Educational Brief" was based upon your judgment that the information presented in the Brief was an update to a January 19, 2001, "Dear Colleague" letter that had been reviewed by FDA prior to its issuance. You further stated that the Agency did not consider the 2001 "Dear Colleague" letter to be a correction or removal at that time. In addition, you stated that the revised labeling contained in the July 2003 Educational Brief had been previously reviewed by FDA as part of PMA Supplement P860004/S053, which was approved by FDA on October 9, 2002. Your firm indicated that the July 2003 Educational Brief did not constitute additional information beyond the approved labeling in the PMA Supplement.

FDA disagrees with your conclusion that the July 2003 Educational Brief was not a correction or removal. Although the Educational Brief contained language consistent with the approved labeling in PMA Supplement P860004/S053, this new labeling had not been previously communicated to physicians whose patients already had a SynchroMed pump implanted within them. Note that the 21 CFR Part 806 definitions and requirements do not depend upon whether the revised labeling in the July 2003 Education Brief had gone through the PMA supplement process or that FDA had prior knowledge of the information through a PMA supplement. Your firm is required to review each corrective action and/or removal and determine whether the requirements of the regulation have been met and thus require a report. Providing the information to FDA via another requirement does not abrogate your responsibility to comply with the requirements of 21 CFR Part 806. If your firm determines that the event in question is not reportable, you must provide an explanation of your decision not to submit a Corrections and Removals report and keep a record of this justification, as required by 21 CFR 806.20.

Our inspection also revealed that your firm has several procedures for Medical Device Reporting and Adverse Drug Experience Reporting. These procedures, in turn, reference several other procedures. Your firm's current problems regarding MDR reporting, as discussed above in this Warning Letter, may be exacerbated by the complexity of your procedures and might have contributed to your firm's deviations from the regulations regarding MDR reporting.

In addition, the inspection revealed several ongoing violations in your quality system that were also noted in the 483. In particular, you have failed to achieve consistent compliance in areas such as design controls (21 CFR 820.30) and corrective and preventive action (21 CFR 820.100). These areas had previously been found not to be in compliance during the inspection performed from May 18 through June 22, 2006. These quality system violations were also cited in an August 29, 2006, Warning Letter that was sent to you. By letter dated June 4, 2007, George Aram, Vice President of Quality, Neurological Sector, provided an update on the status of the corrective actions taken and planned by your firm to address these violations. In that letter, Mr. Aram stated that the longest remediation activities extend into November 2007. We encourage you to expedite your efforts to achieve full compliance and to keep us informed of your progress.

In your firm's June 4, 2007 response, you also indicated that your Risk Evaluation Board (REB) met on May 10, 2007, to [redacted]

This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure compliance with the Act and regulations. The specific violations noted in this letter and in the Form FDA 483 issued at the close of the inspection may be symptomatic of serious underlying problems in your firm's manufacturing and quality assurance systems. You are responsible for investigating and determining the causes of the violations identified by he FDA. You also must promptly initiate permanent corrective and preventive action to bring your products into compliance.

Federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, no premarket approval applications for Class III devices to which the Quality System regulation deficiencies are reasonably related will be approved until the violations have been corrected. Also, no requests for Certificates to Foreign Governments will be granted until the violations related to the subject devices have been corrected.

You should take prompt action to correct the deviations described in this letter. Failure to promptly correct these deviations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties.

Please notify this office in writing within 15 working days to acknowledge receipt of this letter and to provide an update on the status of your corrective actions. Your response should be sent to Timothy G. Philips, Compliance Officer, at the address on this letterhead.

Sincerely,

/S/

W. Charles Becoat
Director
Minneapolis District

TGP/ccl

______________________________________________________________________

1At the time of the FDA's inspection, the establishment was known as Medtronic Neurological.